Solvent Drives Switching between Λ and Δ Metal Center Stereochemistry of M8L6 Cubic Cages

An enantiopure ligand with four bidentate metal-binding sites and four (S)-carbon stereocenters self-assembles with octahedral ZnII or CoII to produce O-symmetric M8L6 coordination cages. The Λ- or Δ-handedness of the metal centers forming the corners of these cages is determined by the solvent environment: the same (S)-ligand produces one diastereomer, (S)24-Λ8-M8L6, in acetonitrile but another with opposite metal-center handedness, (S)24-Δ8-M8L6, in nitromethane. Van ’t Hoff analysis revealed the Δ stereochemical configuration to be entropically favored but enthalpically disfavored, consistent with a loosening of the coordination sphere and an increase in conformational freedom following Λ-to-Δ transition. The binding of 4,4′-dipyridyl naphthalenediimide and tetrapyridyl Zn-porphyrin guests did not interfere with the solvent-driven stereoselectivity of self-assembly, suggesting applications where either a Λ- or Δ-handed framework may enable chiral separations or catalysis.

UV-vis measurements were employed to fine-tune the solution concentration for subsequent CD measurements, and were performed on a Varian Cary 400 scan UV-vis spectrophotometer with a 1 mm path-length cuvette at 298 K. Circular Dichroism was performed on an Applied-Photophysics Chirascan CD spectrometer using a 1 mm path-length cuvette. Experiments were recorded at 298 K, maintained with a Peltier temperature control. Measurements were background subtracted from blank solvent in an identical cuvette. The sample concentrations were adjusted to maintain a HV below 800 V.

S4
Low resolution electrospray ionization mass spectrometry was undertaken on a Micromass Quattro LC mass spectrometer (cone voltage 20-50 eV; desolvation temp. 40 °C; ionization temp. 40 °C) infused from a Harvard syringe pump at a rate of 10 μL/min. A microwave reactor from Discover SP-D 80-CEM Corporation was used for the encapsulation of tetrapyridyl Zn-porphyrin by Zn8L6 cage.

Synthesis and Characterization of Ligand A 2.1 Synthesis of Enantiopure 2-Ethynylpyridine (S4)
A suspension of 2-bromonicotinic acid (2.02 g, 10.0 mmol, 1.0 equiv) in SOCl2 (15 mL) was heated to reflux at 80 °C for 2 hours. After cooling down to room temperature, excess SOCl2 was evaporated under reduced pressure, and Et3N (2.02 g, 20.0 mmol, 2.0 equiv) in CH2Cl2 (20 mL) was subsequently added. The solution was then cooled to 0 °C , and (S)-3,3-dimethyl-2-butylamine (1.01 g, 10.0 mmol, 1.0 equiv) was added over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The resulting suspension was washed with brine (20 mL) and saturated aqueous NaHCO3 solution (20 mL). The combined aqueous phases were extracted with CH2Cl2 (2 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the solvents were evaporated under reduced pressure. The crude compound S2 was obtained as a pale yellow solid (2.22 g, 78% yield over 2 steps) and used without purification. subsequently added, and the reaction mixture was stirred for 1 hour at room temperature. Brine (50 mL) was then added, and the suspension was extracted with CH2Cl2 (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the solvents evaporated under reduced pressure. Purification by flash column chromatography on silica gel using hexane/EtOAc = 2/3 as eluent afforded S4 as a brown solid (807 mg, 70% yield over 2 steps).   Figure S2. 13 C NMR spectrum of compound S4 (400 MHz, CDCl3, 25 °C ).
Cage 1 consists of a pair of diastereomers, with each having either eight Δ or eight Λ zinc vertices. According to the 1 H NMR spectrum, the accurate diastereomeric ratio (d.r.) was determined to be 3.8:1. Based on the assumption that the major diastereomer has crystallized from MeCN, X-ray crystallographic analysis allowed identification of the absolute configuration of the major diastereomer. The major diastereomer was identified to be (S)24-Λ8-1, while the minor diastereomer is (S)24-Δ8-1.
Cage 2 consists of a pair of diastereomers, with each having either eight Δ or eight Λ zinc vertices. According to the 1 H NMR spectrum, the accurate diastereomeric ratio (d.r.) was determined to be 3.6:1. Based on the assumption that the major diastereomer has crystallized in MeCN, X-ray crystallographic analysis allowed identification of the absolute configuration of the major diastereomer. The major diastereomer was identified to be (S)24-Λ8-1, while the minor diastereomer is (S)24-Δ8-1.   (Table S1 and Figure S24). In CD3CN, (S)24-Λ8-1 was predominantly formed, while (S)24-Δ8-1 was the major diastereomer in both CD3NO2 and CD3COCD3.
The diastereomeric ratios were determined by 1 H NMR integration. Stereochemical outcomes were further confirmed by CD spectra ( Figure S25). Cage 1 formed in MeCN displayed negative Cotton effects corresponding to Soret and Q bands, whereas positive signals were observed for cage 1 in both MeNO2 and acetone.  Figure S24. 1     Step 2: CD3CN was evaporated and CD3NO2 (0.5 mL) was added; the 1 H NMR spectrum was then measured (d.r. = 3.8:1) after being kept at 25 °C for 10 minutes.
It was observed that the diastereoselectivity could be easily switched by changing solvents ( Figure S30). These observations indicated that the (S)24-Λ8-1⇄(S)24-Δ8-1 interconversion is a reversible process controlled by the solvent.       Cage was formed in acetonitrile with a diastereomeric ratio of (S)24-Λ8-1:(S)24-Δ8-1 = 3.8:1. The acetonitrile solution of cage 1 could be stored at 25 °C for six months with no changes in the diastereomeric ratio, and no decomposition was observed for the cage.
Cage 1 was not able to encapsulate tetrapyridyl Zn-porphyrin (G2) in nitromethane, due to the insolubility of G2 in nitromethane. Inspired by the solvent-dependent diastereocontrol for this dynamic system, we attempted to dissolve the solid-state G21 in nitromethane. As expected, a reverse diastereoselectivity was observed.
According to the 1 H NMR spectrum, the diastereomeric ratio (d.r.) was determined to
The shifts of Hβ and Hγ indicated that the binding process is within complex G21.
However, cage 1 was not able to bind 4,4'-bipyridine with no changes in chemical shifts for the host (Figure 72).

Non-Binding Guests
Prospective guests (1.0 μmol, 5 equiv) and cage 1 (3.46mg, 0.2 μmol, 1.0 equiv) were combined in CD3CN (0.5 mL) in NMR tubes. The reaction mixtures were heated at 70 °C for 16 hours. After cooling down to room temperature, 1 H NMR and 19 F NMR spectra were measured within 4 hours. No changes in chemical shift were observed for the following guests.

X-ray Crystallography
Data were collected at Beamline I19 of Diamond Light Source employing silicon double crystal monochromated synchrotron radiation (0.6889 Å) with ω and ψ scans at 100(2) K. 5 Data integration and reduction were undertaken with Xia2. 6 Subsequent computations were carried out using the WinGX-32 graphical user interface. 7 Absorption corrections were applied to the data using the AIMLESS 8 tool in the CCP4 suite. 9 The structures were solved by intrinsic phasing using SHELXT 10 then refined and extended with SHELXL. 11 In general, non-hydrogen atoms with occupancies greater than 0.5 were refined anisotropically. Carbon-and nitrogen-bound hydrogen atoms were included in idealised positions and refined using a riding model.
Oxygen-bound hydrogen atoms were first located in the difference Fourier map before refinement where possible. Disorder was modelled using standard crystallographic methods including constraints, restraints and rigid bodies where necessary.
Crystallographic data along with specific details pertaining to the refinement follow.
Crystallographic data have been deposited with the CCDC (2115416 and 2115489). Due to relatively high levels of thermal motion present throughout the structure bond lengths and angles within pairs of chemically identical organic ligand arms were restrained to be similar to each other (SAME). Thermal parameter restraints (SIMU, RIGU) were applied to all atoms except for zinc to facilitate anisotropic refinement.
Five of the eight crystallographically unique tert-butylmethylamide substituents could be readily resolved but the remaining three were substantially disordered and required extensive restraints to facilitate realistic modelling. The GRADE program 13 was employed using the GRADE Web Server 14 to generate a full set of bond distance and angle restraints (DFIX, DANG, FLAT) for the organic ligand arms, which were then applied to the disordered tert-butylmethylamide substituents and where necessary to other parts of the structure showing high degrees of thermal motion. The disordered tert-butylmethylamide substituents were modelled isotropically. Even after modelling as disordered over two locations, the thermal parameters of some of these groups and several other outer substituents and tetrafluorophenyl rings remain larger than ideal as a result of significant thermal motion (or dynamic disorder) resulting in a high Ueq min/max range for the main residue.

S66
The porphyrin zinc atoms and coordinated water molecules were modelled as disordered over two positions on opposite sides of the porphyrin ring with equal occupancies. The hydrogen atoms of the water molecules were first located in the electron density map and then refined with bond length and angle restraints.
Hydrogen bond acceptors were not located for any of the water molecules, presumably due to the highly disordered nature of the surrounding anions and solvents within the structure, giving rise to several B-level Checkcif alerts.
The anions and solvent molecules within the structure show evidence of disorder. One triflimide anion was modelled as disordered over two locations and two further triflimides were modelled with partial occupancy and their occupancies refined. Diffuse solvent molecules could not be assigned to acetonitrile or diethyl ether and were therefore not included in the formula. Consequently, the molecular weight and density given above are underestimated.
CheckCIF gives 1 A level alert due to isotropic modelling of the disordered substituents and 11 B levels alerts, mostly arising from water molecules missing hydrogen bond acceptors as well as the acetonitrile molecule for which hydrogen treatment of disorder. An initial solution was thus obtained using the structure of the Zn(II)-cornered analogue. The absolute configuration of the structure was confirmed using anomalous dispersion effects and the Flack parameter 12 refined to 0.087 (7).
The small deviation from zero can be explained by the high degree of disorder and thermal motion within the structure.
Due to the less than ideal resolution and high levels of thermal motion present throughout the structure the restraints, calculated using the GRADE program 13 as described above were applied to all of the ligand arms. Thermal parameter restraints (SIMU, RIGU) were applied to all atoms except for zinc and cobalt to facilitate anisotropic refinement. Five of the eight crystallographically unique tert-butylmethylamide substituents were modelled as disordered over two locations and the disordered substituents were modelled isotropically.
The porphyrin zinc atoms were disordered over two positions on opposite sides of the porphyrin ring with equal occupancies and some of their coordinated water molecules were modelled with partial occupancy. The hydrogen atoms of the water molecules could not be located in the electron density map and were not included in the model.
The anions and solvent molecules within the structure show evidence of disorder. One triflimide anion was modelled as disordered over two locations and the occupancies of the other located triflimides were refined; any additional minor occupancy disorder positions of these anions could not be resolved. Substantial bond length and thermal parameter restraints were applied to facilitate a reasonable refinement of the anions.
Even with these restraints some atoms in the triflimide anions show larger than ideal thermal parameters suggesting further dynamic disorder.
Further reflecting the solvent loss there is a significant amount of void volume in the lattice containing smeared electron density from disordered solvent and ca. 5.2 anions per Co8L6 assembly (assigned to triflimide in the formula). Consequently, the SQUEEZE 15 unction of PLATON 16 was employed to remove the contribution of the electron density associated with these remaining anions and further highly disordered solvent, which gave a potential solvent accessible void of 36565 Å 3 per unit cell (a total of approximately 8395 electrons). Diffuse solvent molecules could not be Supporting Information S69 assigned to acetonitrile or diethyl ether and were therefore not included in the formula.
Consequently, the molecular weight and density given above are underestimated.
CheckCIF gives 2A level alert and 4B levels alerts. These alerts arise from the limited resolution, isotropic modelling of the disordered substituents and anions showing thermal motion/dynamic disorder.  Supporting Information
The separated Ha signals at low temperatures allowed us to determine the diastereomeric ratio of the ZnL3 complex in both CD3CN and CD3NO2. In both solvents, the d.r. was determined to be 1.3:1, and the solvent-dependent stereochemical inversion phenomenon was not observed. Due to the low diastereoselectivity, weak Cotton effects were observed in CD spectra of ZnL3 in MeCN; CD and UV spectra of ZnL3 could not be measured in MeNO2 due to the strong background signal from MeNO2 (200-350 nm).
The above results indicated that the energy difference between the cage diastereomers emerges as a consequence of higher-order assembly.